Do Not Disturb: Probiotics Aren’t There Yet

When considering the role of probiotics in altering the gut microbiome, we have more questions than answers. While my colleague has dutifully pointed out the promise, I have outlined a few problems we would be irrational to ignore.

We recently performed a survey of patients with celiac disease concerning the use of complementary and alternative medicine.1 Among the respondents, 24 percent claimed they used one or more forms of complementary and alternative medicine, and probiotics were the most frequently used. In this study, these subjects had more symptoms than those who did not take this approach, though they also had a higher quality of life.

Probiotics are manufactured and marketed as dietary supplements. The Dietary Supplement Health and Education Act of 19942 effectively minimized regulation by FDA for any product labeled as a dietary supplement. These products are not subject to FDA’s rigorous standards of testing, controlled studies and safety requirements like drugs are. Recent articles in the New York Times, including an editorial,3 highlight the state of the dietary supplement industry. In the editorial the description of testing various herbal supplements using bar code DNA testing found that four out of five of the herbal supplements tested did not actually include any of the herbs listed on their labels.4

These studies led the New York state attorney general to issue cease and desist orders to four major retailers concerning the sale of these dietary supplements; other states arepursuing the same course. This was the culmination of previous articles in the New York Times that referred to the work of Newmasteret al.,4 who used bar code DNA testing to demonstrate an alarmingly high rate of product substitution, contamination and use of unlabeled, potentially dangerous (to some patients) fillers in commercially obtained herbal supplements in North America. There was a high rate of the presence of products such as rice, wheat and noxious herbs, none of which were on the label. This is hardly a vote of confidence for the industry and its products. The sources were varied and the findings were across products from different suppliers and of different price ranges.

Our study and these recent articles in theÂ New York TimesÂ prompted us to wonder whether there could be gluten in probiotics that may be contributing to the increase in symptoms.

Our study cited above, and these recent articles inÂ the New York Times, prompted us to wonder whether there could be gluten in probiotics that may be contributing to the increase in symptoms in patients with celiac disease who use probiotics. In light of this, we purchased probiotics of a range of prices and from various sources including Amazon.com, store brandsfrom pharmacies and one through a prescription. We then examined them for gluten using liquid chromatographymass spectrometry;5 gluten from wheat, rye and/or barley was detected in about half of them. There were greater than 20 parts per million of gluten” the FDA allowed concentration of gluten below which is regarded as being gluten-free” in several, including some that were labeled gluten-free. However, it is not clear if the small amount of gluten that people with celiac disease taking these products would consume is harmful. For instance, gluten challenge studies reveal that patients exhibit varying degrees of sensitivity to different doses of gluten, however some people with celiac are sensitive to very small quantities.6 In addition, there is evidence that after a period on the gluten-free diet patients may become more sensitive to small amounts of gluten compared to the time of original diagnosis. The presence of gluten in probiotics labeled gluten free is concerning to those who need to avoid gluten, as they are typically vigilant about everything they consume, and this indicates that they cannot always trust the labels of some products.

Other factors to consider with probiotics include contamination with pathogenic organisms and their safety in the immunocompromised individuals. The death of a newborn child in a Connecticut hospital due to the fungal contamination of a prescribed probiotic prompted an official CDC health advisory.7 How often are probiotics contaminated with other organisms, such as Candida, that are obviously not on the label? What quality control measures to determine if contamination exists are practiced by manufacturers? Newborns are considered immunocompromized. Bacteremia due to the specific administered probiotic has been reported in pre-term babies administered probiotics to prevent necretizing enterocolitis.8,9 How widely are newborns prescribed a probiotic in the hospital setting? What probiotic does the hospital pharmacist acquire and from where, the corner drug store? Bacteremia has been reported in children with short bowel syndrome as well.10 Though generally considered safe in children,11 studies vary in quality and there are questions as to whether adverse events are adequately reported.The use of probiotics in newborns is controversial.12 Another important question is if probiotics should be given to patients taking immunosuppressants or immunomodulatory agents? Patients usually don’t volunteer information about medications that are not prescribed as they are not considered medications, merely dietary supplements, so there is a danger that we are not aware of a potential problem. Cochrane analyses of probiotic use in ulcerative colitis reveal them to be generally safe without increase in adverse effects.13, 14

However, recent reports of bacterium due to Lactobacillus species that are identical to that in the probiotic in patients with active colitis receiving steroids and immunosuppressive agents, raises concern for their use in seriously ill patients.15 Studies have used probiotics in patients with IBS, IBD and celiac disease. No doubt these specific probiotic samples were supplied by the manufacturer. One also wonders whether the probiotics available to consumers are of the same standard asthose supplied to the investigators. Additionally, I was struck by the fact that only five of the 22 probiotics we purchased in our study had an advisory that they should be refrigerated. This raises further questions about the viability of the organisms in the capsules that are supplied to the consumer. What is the shelf life? Does refrigeration make a difference? At what rate does viability decline and does this matter, as dead microorganisms may convey some health benefit?

Certainly we are all very excited to learn about the microbiome and its role in disease, especially gastrointestinal issues. This knowledge will lead to new therapies that may allow us to alter the microbiome in a beneficial way. However, are we there as yet with our currently available probiotic products? I do not think so. With the questions raised above, I wonder whether we should be advising the use of products that we know so little about, including their manufacturing processes and efficacy. They are not regulated like the other medications we prescribe, so maybe we should be advising patients to avoid them.

Dr. Green serves on the scientificÂ advisory boards of AlbaÂ Therapeutics and ImmusanT. HeÂ also serves as the president of theÂ North American Society for theÂ Study of Celiac Disease.